Dengue is a globally important arbovirus transmitted by the aedes mosquito, with an estimated 100 million cases a year worldwide. Cases of dengue can be found in nearly all countries between the tropics of Cancer and Capricorn, with large yearly outbreaks in South East Asia and South America.

Vector control of the Aedes mosquito is challenging and dengue is seen as an emerging global threat.

Dengue largely affects the paediatric population but can present in adults. There is no human to human transmission.

Dengue virus is a single-stranded RNA flavivirus with 4 different but closely related serotypes. It is contracted by a bite from an infected Aedes mosquito. Dengue cannot be transmitted from person to person directly.

Aedes mosquitos are found throughout the tropics, which means dengue is endemic in many countries including:

• Africa
• The Americas
• Western Pacific
• South-East Asia

The main vector for dengue is the Aedes aegypti mosquito. There are also some other Aedes species including Aedes albopictus which can transmit dengue.

The Aedes mosquito is typically found in urban settings, increasing human exposure and risk of contracting dengue. The mosquitos:

• Rest and breed indoors
• Lay eggs in containers e.g. tyres
  • Very drought-resistant eggs
• Limited flight range (<100m)
• Prefer to bite humans
• Diurnally active
  • Bed nets less effective

The major risk factors for developing dengue are:

• Visiting a dengue-endemic region
• High population density
• Poor standards of hygiene

Severe dengue is more likely to develop in:

• Children under 15 years old
• Repeated dengue infections
• Specific viral genotypes
• Malnourished children.

Dengue virus is the most important arbovirus worldwide. It is:

• Single-stranded RNA virus
• Within Flavivirus genus
• Has 4 different but closely related serotypes (DEN-1, DEN-2, DEN-3, DEN-4)
  • May also be 5th genotype
• DEN-2 and DEN-3 (Asian serotypes) often associated with severe disease
  • Especially if the dengue infection is a secondary infection.

Dengue has a 4-10 day incubation period after the bite from an infected mosquito. Viral multiplication occurs in macrophages, monocytes, and B cells. Can also happen in mast cells, dendritic cells, and endothelial cells. Patients can only transmit the infection via the Aedes for 4-5 days (maximum 12 days).

• No direct human to human transmission

Lifelong immunity to 1 specific viral serotype develops after infection. However, there is an increased risk of severe dengue in subsequent infections with different serotypes. This is called antibody-dependent enhancement.

• Unclear mechanism
• Only in 2-4% of patients

Initial presentation of dengue is with flu-like illness

• Fever typically starts on day 3
• Lasts for 5-6 days (viraemic phase)
  • Can then recover or progress to severe dengue
• Mild haemorrhagic symptoms
• Dengue fever is rarely fatal

The major pathophysiological process in severe dengue is increased vascular permeability due to capillary leakage causing plasma leakage into tissues. This leads to:

• Cytokine response
• Suppression of T- cell response

Dengue can be asymptomatic (75%) or present as a non-specific febrile illness (25%), especially in young children. Dengue has a broad clinical spectrum ranging from a mild flu-like illness to severe haemorrhagic, shock and multi-organ failure.

The current classification system is the 2009 World Health Organisation scheme described below. This has superseded the previous classifications of dengue fever, dengue haemorrhagic fever and dengue shock syndrome.

1. Non-severe dengue: fever followed by recovery

Without warning signs

• Fever with two of the following:
  • Nausea/vomiting
  • Rash
  • Aches and pains
  • Positive tourniquet test
  • Leukopenia

With warning signs

• Abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy, restlessness, liver enlargement >2cm, increasing haematocrit with reducing platelets

The initial presentation of dengue is:

• Intermittent high pyrexias ‘break-bone fever’ lasting 3-7 days
• Arthralgia
• Rash
  • Typically blanching maculopapular erythematous rash similar to measles or scarlet fever
  • May develop into petechiae
• Other bleeding manifestations including
  • Bleeding gums
  • Epistaxis
  • GI bleeds

Other features may be quite non-specific and can include:

• Headache
• Nausea & vomiting
• Lymphadenopathy
• Generalised myalgia
• Backache
• Ocular manifestations:
  • Retro-orbital pain
  • Conjunctival injection
  • Conjunctivitis

2. Severe dengue (5% of patients) dengue with severe plasma leakage, severe haemorrhage and severe organ impairment.

Severe symptoms may include:

• Pulmonary and facial oedema
• Ascites
• Pleural effusions
• Meningism including photophobia
• Worsening or more profuse haemorrhage

The investigations used will depend on the resources available and the clinical setting but the majority of investigations are likely to be performed in secondary care.

Blood tests tend to show thrombocytopenia (up to 80%, although may be mild) and leucopenia (also up to 80%, tends to improve after day 5) for the majority of all patients (severe and non-severe). Haematocrit can be a useful monitoring tool, with increasing haematocrit often reflective of clinical deterioration.

Other bloods may show:

• Prolongation of APTT and PT
• Deranged U&E's
• Elevated LFTs especially AST

Diagnosis can be confirmed by:

• Viral isolation from serum
  • Sample needs to be collected early during the viraemic period (before day 5)
• PCR (where available)
• Antibody detection using ELISA: IgM and IgG
  • Can be used after day 5
  • Form used in rapid testing kits
  • Allow distinguishing of primary (first flavivirus exposure) from secondary (previously exposed to different flavivirus)

The tourniquet test can also be used but is only positive about 1/3 of patients, with a specificity of 71%. It can be used in low resource settings with limited access to serological testing.

• Inflate a BP cuff to halfway between systolic and diastolic pressure for 5 mins
  • A positive test shows 20+ petechiae in a 2.5cm square on the forearm

The differential diagnosis can be incredibly broad and will vary depending on the stage of clinical presentation. A clear travel history is vital for these patients.

Dengue often presents with a mild flu-like illness which may be difficult to separate from many other common viral illnesses in UK practice.

• Consider travel history and vaccination status

Common UK viral illnesses may include:

• Influenza
• Infectious mononucleosis
• Enterovirus
• Measles
• Rubella

Common and important tropical infections to consider include:

Viral

• Chikungunya
  • Joint swelling more prominent feature
• Zika
  • Often mild or no fever
  • Purulent conjunctivitis
• Other viral haemorrhagic fevers e.g. Lassa fever, Ebola
  • Often geographically localised, especially in West Africa
• Acute HIV seroconversion
  • Consider risk factors for HIV e.g. high risk sexual activities

Parasitic

• Malaria

Bacterial

• Typhoid
  • Often presents with GI symptoms
• Rickettsia infections (typhus, scrub typhus)
• Leptospirosis
  • Consider water exposure
• Meningococcal septicaemia
  • Meningism
  • Consider immunisation history and contact exposure

Other

• Autoimmune diseases (e.g. SLE)
• Adverse drug reaction

Patients presenting with suspected dengue fever should be seen or discussed with the infectious disease team to exclude other differentials, and because of the risk of clinical deterioration.

There is no specific treatment for dengue. Antivirals and steroids have not been shown to improve outcomes.

There is no direct human to human transmission so no requirement for isolation.

Non-severe cases:

• Conservative treatment with oral fluid and paracetamol
• Avoid aspirin
  • Increased haemorrhage risk
  • Should also be avoided in children due to risk of Reye's syndrome

Severe cases (uncommon in returned travellers):

• IV fluids
  • Used to restore circulatory volume due to plasma leakage into third space
• Regular observation and monitoring of haematocrit, platelets and renal function
• May require High Dependency or Intensive Care

Deterioration may be rapid (over several hours)

• Severe GI haemorrhage
  • Rare
  • Will require blood transfusion +/- FFP

Preventative measures:

• Use of personal protection equipment
• DEET
  • Long-sleeved clothing
• Vaccine but it is not currently recommended for use
  • Potential to precipitate more severe cases of dengue in people who have been immunised.

The major complication is the potential development of severe dengue. This presents with severe multi-organ involvement, haemorrhage and shock.

• 50% mortality rate if untreated.
  • Reduced to under 5% with treatment.

The usual mortality rate of dengue is <1%.

Patients can also develop:

• Hepatic failure
• Encephalopathy
• Myocarditis
• Disseminated intravascular coagulation
• Septicaemia